Familial Adenomatous Polyposis (FAP) is an autosomal dominant disease in which affected individuals develop hundreds to thousands of benign colorectal tumors (adenomas). Some of these tumors, if not removed, invariably progress to malignancy (carcinomas). Recently, a candidate tumor suppressor gene from chromosome 5q21, APC.sup.1, was isolated and implicated in the development of FAP (Kinzler, K. W. et al., Science 253:661-665 (1991); Nishisho, I., et al., Science 253:665-669 (1991); Groden, J., et al., Cell 66:589-600 (1991); Joslyn, G., et al., Cell 66:601-613 (1991)). Further analyses of the APC gene in 150 kindreds indicate that APC mutations can account for most if not all cases of FAP (Miyoshi, Y., et al., Proc. Natl. Acad. Sci. USA 89:4452-4456 (1992)).
Carcinomas in FAP patients, however, account for less than 1% of all colorectal cancers. Most colorectal cancers do not have a well recognized inherited basis and therefore are classified as sporadic. Recent studies have indicated that the majority of these sporadic tumors have somatic mutations of the APC gene (Miyoshi, Y., et al., Human Molecular Genetics 1: 229-233 (1992); Powell, S. M., et al., Nature 17:235-237 (1992)). Furthermore, these mutations appear to occur early during colorectal tumorigenesis and have been detected in tumors as small as 0.5 cm in diameter (Powell, S. M., et al., Nature 17:235-237 (1992)). The nature of the mutations identified in sporadic tumors and in FAP patients is striking, with greater than 94% of the mutations predicted to result in truncation of the APC gene product. Taken together, the above studies indicate that APC plays an important and early role in the development of the major forms of colorectal neoplasia.
The APC gene contains an 8,538 bp open reading frame (ORF) and is predicted to encode a 2,843 amino acid polypeptide with few homologies to other proteins (Kinzler, K. W., et al., Science 253:661-665 (1991); Groden, J., et al., Cell 66:589-600 (1991)). The large size of the APC coding region makes identification of mutations in patients labor intensive and costly. Therefore, there is a need in the art for a quicker, less expensive method for identifying patients who carry a mutant APC allele.